GDP-mannose 4,6-dehydratase

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GDP-mannose 4,6-dehydratase
Identifiers
EC number 4.2.1.47
CAS number 37211-59-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO

In enzymology, a GDP-mannose 4,6-dehydratase (EC 4.2.1.47) is an mannosyltransferase enzyme that catalyzes the chemical reaction

GDP-mannose GDP-4-dehydro-6-deoxy-D-mannose + H2O

Hence, this enzyme has one substrate, GDP-mannose, and two products, GDP-4-dehydro-6-deoxy-D-mannose and H2O.

This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is GDP-mannose 4,6-hydro-lyase (GDP-4-dehydro-6-deoxy-D-mannose-forming). Other names in common use include guanosine 5'-diphosphate-D-mannose oxidoreductase, guanosine diphosphomannose oxidoreductase, guanosine diphosphomannose 4,6-dehydratase, GDP-D-mannose dehydratase, GDP-D-mannose 4,6-dehydratase, Gmd, and GDP-mannose 4,6-hydro-lyase. This enzyme participates in fructose and mannose metabolism. It employs one cofactor, NAD+.

GDP-Mannose 4, 6-Dehydratase Reaction[edit]

GDP-D-Mannose.svgThe enzyme GDP-Mannose 4, 6-Dehydratase which is in the lyases family of enzymes, specifically the hydro-lyases. Other names in use include guanosine 5'-diphosphate-D-mannose oxidoreductase, guanosine diphosphomannose oxidoreductase, guanosine diphosphomannose 4,6-dehydratase, GDP-D-mannose dehydratase, GDP-D-mannose 4,6-dehydratase, GMD, and GDP-mannose 4,6-hydro-lyase. The enzymes is a part of the GDP-Fucose de novo pathway is the first step in the catalyzing process that gives us GDP-Fucose which is crucial in Fucose biosynthesis. In its structure it contains 372 amino acids. By catalyzing GDP-Mannose we acquire GDP-Fucose and fucosyltransferases which play a major roles in cell immunity and signaling. Currently GDP-Mannose 4, 6-Dehydratase is not the target of any available drugs, however it is being experimentally tested in the drug Guanosine-5'-Diphosphate. The chemical reaction of GDP-Mannose 4, 6-Dehydratase is as shown:

GDP-mannose ↔ GDP-4-dehydro-6-deoxy-D-mannose + H2O

Factors In The Reaction[edit]

The enzymes substrate, what the enzyme is acting on, is the GDP-Mannose substance. No other substrates are use this enzyme for reactions.

When the enzyme undergoes its catalyzing process the main product is gets is when it converts GDP-mannose to GDP-4-dehydro-6-deoxy-D-mannose which is then subsequently converted to GDP-Frucose which is crucial for the body to process correctly. It acts as an intermediate step between GDP-Mannose and GDP-Frucose.

In the reaction that the enzyme uses it requires only one cofactor, a compound required for activation, which is NADP(+) however it is uncertain if this compound truly activates the enzyme.

The enzyme GDP-Mannose 4, 6-Dehydratase has no known inhibitors.

Here is a pymol view of the entire structure of the GDP-Mannose 4, 6-Dehydratase enzyme.

GDP-Fucose Biosynthesis Pathway[edit]

The enzyme GDP-Mannose 4, 6-Dehydratase is only present in one pathway that we know of. This pathway is the GDP-mannose-dependent de novo pathway which provides most of the bodies GDP-Fucose whereas minor amounts come from fucose salvaging in the body.

Here we can see the full crystal structure of the GDP enzyme. Use this link to find the subunits of the enzyme http://www.rcsb.org/pdb/explore/jmol.do?structureId=1RPN&opt=3 PDB 1rpn

In the pathway the enzyme is in an intermediate step that that converts GDP-Mannose to GDP-4-dehydro-6-deoxy-D-mannose which is then converted into GDP-Fucose which is absolutely crucial to the body. The product of this pathway is fucosyltransferases which is then used in a different pathway that creates fucosylated glycans which is used for cell signaling and immunity in the body. Fucose is a deoxyhexose that is present in a wide variety of organisms. In most mammals, fucose-containing glycans have important roles in blood transfusion reactions, selectin-mediated leukocyte-endothelial adhesion, host-microbe interactions, and numerous ontogenic events. Along with those the body uses fucose as signaling branches of a cell and also as identification systems in immunity. However the enzyme only works at its top levels under normal body conditions. Increased pH or heat could severely denature the protein causing the enzyme to malfunction.

GDP-Mannose 4, 6-dehydratase Structure[edit]

In the enzyme it contains four different subunits. Each of these units helps to make up the quaternary structure of the protein that allows the enzyme to function correctly. Here is a link for a 3-D view of the enzyme http://www.rcsb.org/pdb/explore/jmol.do?structureId=1RPN&bionumber=1

Homology[edit]

In recent years testing has been done on mice genes and some other mammals that also had GDP-Mannose 4, 6-Dehydratase converting GDP-4-6-deoxymannose to GDP-fucose. Scientists have found that the same gene producing the GDP enzyme is 61% similar in mice to that of humans therefore making it the most homologous with humans.

Structural studies[edit]

As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1DB3, 1N7G, 1N7H, 1RPN, and 1T2A.

References[edit]

  • Elbein AD & Heath EC (1965). "THE BIOSYNTHESIS OF CELL WALL LIPOPOLYSACCHARIDE IN ESCHERICHIA COLI. II. GUANOSINE DIPHOSPHATE 4-KETO-6-DEOXY-D-MANNOSE, AN INTERMEDIATE IN THE BIOSYNTHESIS OF GUANOSINE DIPHOSPHATE COLITOSE". J. Biol. Chem. 240: 1926–31. PMID 14299611. 
  • Liao TH, Barber GA (1972). "Purification of guanosine 5'-diphosphate D-mannose oxidoreductase from Phaseolus vulgaris". Biochim. Biophys. Acta. 276 (1): 85–93. PMID 5047712. doi:10.1016/0005-2744(72)90010-1. 
  • Melo A, Elliott WH & Glaser L (1968). "The mechanism of 6-deoxyhexose synthesis. I. Intramolecular hydrogen transfer catalyzed by deoxythymidine diphosphate D-glucose oxidoreductase". J. Biol. Chem. 243 (7): 1467–74. PMID 4869560. 
  • Sullivan FX, Kumar R, Kriz R, Stahl M, Xu GY, Rouse J, Chang XJ, Boodhoo A, Potvin B & Cumming DA (1998). "Molecular cloning of human GDP-mannose 4,6-dehydratase and reconstitution of GDP-fucose biosynthesis in vitro". J. Biol. Chem. 273 (14): 8193–202. PMID 9525924. doi:10.1074/jbc.273.14.8193. 
  • Kneidinger B, Graninger M, Adam G, Puchberger M, Kosma P, Zayni S & Messner P (2001). "Identification of two GDP-6-deoxy-D-lyxo-4-hexulose reductases synthesizing GDP-D-rhamnose in Aneurinibacillus thermoaerophilus L420-91T". J. Biol. Chem. 276 (8): 5577–83. PMID 11096116. doi:10.1074/jbc.M010027200. 
  • Mulichak AM, Bonin CP, Reiter WD & Garavito RM (2002). "Structure of the MUR1 GDP-mannose 4,6-dehydratase from Arabidopsis thaliana: implications for ligand binding and specificity". Biochemistry. 41 (52): 15578–89. PMID 12501186. doi:10.1021/bi0266683.